Melanoma-Associated Chondroitin Sulfate Proteoglycan (MCSP), also referred to as “high molecular weight melanoma associated antigen” (HMW-MAA), “human melanoma proteoglycan” (HMP), “melanoma-associated proteoglycan antigen” (MPG) and “melanoma chondroitin sulfate proteoglycan” (mel-CSPG), is a glycoprotein-proteoglycan complex consisting of an N-linked glycoprotein of 250 kDa and a proteoglycan component >450 kDa. The core glycoprotein is present on the surface of melanoma cells, either as a free glycoprotein or modified by the addition of chondroitin sulfate. The structural features of MCSP include three (3) extracellular domains containing a total of ten (10) cysteines (five (5) potential disulfide bridges), fifteen (15) possible N-linked glycosylation sites, and eleven (11) potential chondroitin sulfate attachment sites. The transmembrane segment has a single cysteine, however, the functional significance of that residue has not been established. The cytoplasmic domain has three (3) threonine residues that may serve as sites for phosphorylation by protein kinase C, although it has not yet been shown that MCSP is phosphorylated.
MCSP is uniformly and abundantly expressed in most human melanoma lesions (Ferrone et al. (1988) Radiolabeled Monoclonal Antibodies for Imaging and Therapy Vol. 152, S. C. Srivastava, editor. Plenum Publishing Corp., New York/London. P. 55-73). MCSP has also been implicated in tumor invasion (Iida et al. (2001) J. Biol. Chem. 276:18786-18794). MCSP expression is an ominous prognostic factor in acral letiginous melanoma (Kageshita et al. (1993) Cancer Res. 53:2830-2833) and in nonmelanoma tumors such as infantile acute myeloid leukemia (Hilden et al. (1977) Blood 89:3801-3805).
The need exists for improved therapeutic antibodies against MCSP that are effective at treating and/or preventing tumors comprising cells expressing MCSP.